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00925njm 22002777a 4500 dc Aix, Esther author Gutierrez-Gutierrez, Oscar author Sanchez-Ferrer, Carlota author Aguado, Tania author Flores, Ignacio author 2016 The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc(-/-)) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc(-/-) newborns but rescued in G3 Terc(-/-)/p21(-/-) mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts. J Cell Biol. 2016; 213(5):571-83 10.1083/jcb.201510091 1540-8140 0021-9525 Journal of Cell Biology 27241915 http://hdl.handle.net/20.500.12105/5221 MOUSE HEART TERMINAL TRANSFERASE CARDIAC REGENERATION OXIDATIVE STRESS MAMMALIAN HEART STEM-CELLS PROLIFERATION EXPRESSION CANCER MICE Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation